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Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies.We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0·11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher. We used a margin of 0·78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3 + 3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0·11 and 0·15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881.Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0·76 (95% CI 0·72-0·80) for Stockholm3 and 0·60 (0·54-0·65) for PSA. In the experimental group, a Stockholm3 of 0·11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1·18 [95% CI 1·09-1·28], p0·0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1·22 [0·96-1·55], p=0·053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0·15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0·64 [0·55-0·82]) and fewer biopsy procedures (311 vs 338; 0·92 (0·86-1·03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0·11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3·0%] men tested vs 106 [2·1%] men tested; RP 1·44 [95% CI 1·15-1·81]), lower detection of low-grade cancers (50 [0·7%] vs 73 [1·4%]; 0·46 [0·32-0·66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1·8%] of 1372 vs 41 [4·4%] of 921; p=0·0002) and a lower incidence of admission to hospital (16 [1·2%] vs 31 [3·4%]; p=0·0003) than those in the standard group.The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer.The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Background Endoscopic eradication therapy with radiofrequency ablation (RFA) is effective in most patients with Barrett’s esophagus (BE). However, some patients experience poor healing and/or poor squamous regeneration. We evaluated incidence and treatment outcomes of poor healing and poor squamous regeneration. Methods We included all patients treated with RFA for early BE neoplasia from a nationwide Dutch registry based on a joint treatment protocol. Poor healing (active inflammatory changes or visible ulcerations ≥ 3 months post-RFA), poor squamous regeneration ( Results 1386 patients (median BE C2M5) underwent RFA with baseline low grade dysplasia (27 %), high grade dysplasia (30 %), or early cancer (43 %). In 134 patients with poor healing (10 %), additional time and acid suppression resulted in complete esophageal healing, and 67/134 (50 %) had normal squamous regeneration with 97 % CE-BE. Overall, 74 patients had poor squamous regeneration (5 %). Compared with patients with normal regeneration, patients with poor squamous regeneration had a higher risk for treatment failure (64 % vs. 2 %, relative risk [RR] 27 [95 % confidence interval [CI] 18–40]) and progression to advanced disease (15 % vs. Conclusions In half of the patients with poor healing, additional time and acid suppression led to normal squamous regeneration and excellent treatment outcomes. In patients with poor squamous regeneration, however, the risk for treatment failure and progression to advanced disease was significantly increased.

Anthropogenic waterways and canal systems have been part of the cultural and natural landscape for thousands for years. As of the late 20th century, more than 63 000 km of canals exist worldwide as transport routes for navigation, many with barriers (e.g., locks, dams) that fragment the system and decrease connectivity. Fragmentation alone can have negative implications for freshwater biodiversity; by isolating populations and communities, other human-mediated disturbances associated with canals like poor water quality and invasive species can exacerbate these negative effects. As such, the capacity of these interconnected freshwater systems to support biodiversity is continuously degrading at a global level. One critical, highly complex issue that unites canals worldwide is the challenge of governing these systems in a holistic, unified way to both protect biodiversity and preserve historical elements. Managing historic canals involves multiple objectives across many agencies and stakeholders, often with different or conflicting objectives. Here, we use the Rideau Canal, a UNESCO World Heritage Site and National Historic Site of Canada, as a case study to demonstrate the importance of considering canals as social–ecological systems for effective and efficient governance. Historic canals are integrated systems of both humans (social) and the environment (ecological), linked by mutual feedbacks and coevolution, and must be managed as such to achieve conservation goals while maintaining commemorative integrity. We discuss the history of the Rideau Canal and its current governance, biodiversity in the waterway, different threats and issues (user conflicts, aquatic pollution, shoreline development, water management, species at risk, and invasive species), and conclude by outlining ways to address the challenges of managing it as a coupled social–ecological system. We present different research needs and opportunities that would enable better management, though above all, we propose a shift from the current governance structure — which at best can be considered “patchwork” — to a coordinated, multi-scalar and multi-stakeholder governance regime such that the Rideau Canal can be maintained for its historical integrity without compromising biodiversity conservation. Given that canals are now pervasive worldwide, this article is not only topical to the Rideau Canal, but also to other waterways in Canada and beyond.

Aim: In children with Prader-Willi syndrome (PWS), growth hormone (GH) improves height and body composition; however, may be associated with worsening sleep-disordered breathing (SDB). Some studies have reported less SDB after GH initiation, but follow-up with polysomnography is still advised in most clinical guidelines. Methods: This retrospective, multicentre study, included children with PWS treated with GH at seven PWS treatment centres in Australia over the last 18 years. A paired analysis comparing polysomnographic measures of central and obstructive SDB in the same child, before and after GH initiation was performed with Wilcoxon signed-rank test. The proportion of children who developed moderate/severe obstructive sleep apnoea (OSA) was calculated with their binomial confidence intervals. Results: We included 112 patients with available paired data. The median age at start of GH was 1.9 years (range 0.1–13.5 years). Median obstructive apnoea hypopnoea index (AHI) at baseline was 0.43/h (range 0–32.9); 35% had an obstructive AHI above 1.0/h. Follow-up polysomnography within 2 years after the start of GH was available in 94 children who did not receive OSA treatment. After GH initiation, there was no change in central AHI. The median obstructive AHI did not increase significantly (P = 0.13), but 12 children (13%, CI95% 7–21%) developed moderate/severe OSA, with clinical management implications. Conclusions: Our findings of a worsening of OSA severity in 13% of children with PWS support current advice to perform polysomnography after GH initiation. Early identification of worsening OSA may prevent severe sequelae in a subgroup of children.

ObjectiveRadiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting.DesignEndoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included.ResultsAfter ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk.ConclusionIn a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value.Netherlands trial register numberNL7039.

Background The novel 180° cryoballoon (CbAS180) enables semicircumferential treatment over a length of 3 cm per application. This first-in-human study evaluates its feasibility, efficacy, and safety for the treatment of Barrett’s esophagus (BE) neoplasia. Methods This multicenter study consisted of dose-finding and extension phases. Dose-finding started with the lowest dose possible (1.0 mm/s). For each dose, six patients were treated circumferentially over a 3-cm length. The dose was increased until the median BE regression was ≥ 60 % without serious adverse events (SAEs). In the extension phase, the dose was confirmed in 19 new patients. The outcomes were technical success, BE regression after one treatment, and SAEs. Results 25 patients (median Prague C0M3) were included (6 dose-finding/19 extension). In two patients, the CbAS180 could not be applied because of unstable balloon positioning. The technical success rate was 96 % (22 /23). In the six dose-finding patients, the starting dose resulted in median BE regression of 94 % (95 % confidence interval [CI] 60 %–97 %) without SAEs and was thus considered effective. Overall median BE regression was 80 % (95 %CI 60 %–90 %). Conclusion Single-session CbAS180 seems feasible, safe, and effective, and is a promising technique for the treatment of patients with BE neoplasia.

To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). A prospective European multicenter observational study included women with a singleton pregnancy, 32 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.ZIEL: Beurteilung der longitudinalen Variation der umbilikozerebralen Ratio (UCR) der Pulsatilitätsindizes bei später fetaler Wachstumsrestriktion (FGR). Eine prospektive europäische multizentrische Beobachtungsstudie schloss Frauen mit Einlingsschwangerschaft (32 856 Frauen hatten 2770 Messungen; 696 (81 %) hatten mehr als eine Messung (Median 3, IQR 2–4). Bei Einschluss hatten 63 (7 %) eine UCR ≥ 0,9. Diese entbanden früher und hatten ein niedrigeres Geburtsgewicht und eine höhere Inzidenz für einen unerwünschten Outcome (30 % vs. 9 %, relatives Risiko 3,2; 95 %-KI 2,1–5,0) im Vergleich zu Frauen mit normaler UCR bei Einschluss. Wiederholte Messungen nach abnormaler UCR bei Einschluss waren in 67 % (95 %-KI 55–80) erneut abnormal, aber nach einer normalen UCR betrug die Wahrscheinlichkeit, eine abnormale UCR zu finden, 6 % (95 %-KI 5–7 %). Das Risiko für einen kombinierten unerwünschten Outcome war ähnlich, wenn man den ersten oder den nachfolgenden UCR-Wert verwendete. Eine abnormale UCR ist wahrscheinlich bei einer späteren Messung wieder abnormal, während nach einer normalen UCR die Wahrscheinlichkeit einer abnormalen UCR bei wöchentlicher Wiederholung 5–7 % beträgt. Wiederholte Messungen sagen das Ergebnis nicht besser voraus als die erste Messung, was höchstwahrscheinlich darauf zurückzuführen ist, dass die am stärksten gefährdeten Föten nach einer abnormalen UCR entbunden werden.

Antibody deficiencies constitute the majority of primary immunodeficiencies in adults. These patients have a well-established increased risk of bacterial infections but there is a lack of knowledge regarding the relative risks upon contracting COVID-19. In this monocentric study the disease course of COVID-19 in 1 patient with Good's syndrome and in 13 patients with common variable immunodeficiency (CVID) is described. The severity of disease ranged from very mild to severe. Several patients required hospitalization and immunomodulatory treatment but all survived. Although viral infections are not a typical feature of humoral immunodeficiencies we recommend that vigilance is increased in the management of patients with Good's syndrome and CVID during the COVID-19 pandemic.

Background: Hospitalist physicians are performing fewer procedures because of multiple reasons, including expanded responsibilities beyond their patient panel. A procedure service that offloads hospitalists could expedite these necessary services. An opportunity exists for physician assistants (PAs) and NPs to fill this gap. Objective: To describe the implementation of a PA- and NP-run procedure service at a large academic hospital. Methods: This is a retrospective cohort study of procedures by the procedure service at one institution from 2015 to 2019. Results: Over 5 years, 7,002 procedures were performed, with requests increasing over time. The most frequent procedures were venous access, lumbar puncture, paracentesis, and placement of nasogastric or nasojejunal tubes. Requesting services included hospitalists and residents from internal medicine, surgery, and neurology. Conclusions: A PA- and NP-run procedure service is well accepted at a large academic hospital despite the lack of involvement by attending physicians. Future directions are focused on augmenting coverage and procedures offered.

Introduction: Continuous neurologic assessment in the pediatric intensive care unit is challenging. Current electroencephalography (EEG) guidelines support monitoring status epilepticus, vasospasm detection, and cardiac arrest prognostication, but the scope of brain dysfunction in critically ill patients is larger. We explore quantitative EEG in pediatric intensive care unit patients with neurologic emergencies to identify quantitative EEG changes preceding clinical detection. Methods: From 2017 to 2020, we identified pediatric intensive care unit patients at a single quaternary children's hospital with EEG recording near or during acute neurologic deterioration. Quantitative EEG analysis was performed using Persyst P14 (Persyst Development Corporation). Included features were fast Fourier transform, asymmetry, and rhythmicity spectrograms, “from-baseline” patient-specific versions of the above features, and quantitative suppression ratio. Timing of quantitative EEG changes was determined by expert review and prespecified quantitative EEG alert thresholds. Clinical detection of neurologic deterioration was defined pre hoc and determined through electronic medical record documentation of examination change or intervention. Results: Ten patients were identified, age 23 months to 27 years, and 50% were female. Of 10 patients, 6 died, 1 had new morbidity, and 3 had good recovery; the most common cause of death was cerebral edema and herniation. The fastest changes were on “from-baseline” fast Fourier transform spectrograms, whereas persistent changes on asymmetry spectrograms and suppression ratio were most associated with morbidity and mortality. Median time from first quantitative EEG change to clinical detection was 332 minutes (interquartile range: 201-456 minutes). Conclusion: Quantitative EEG is potentially useful in earlier detection of neurologic deterioration in critically ill pediatric intensive care unit patients. Further work is required to quantify the predictive value, measure improvement in outcome, and automate the process.

Introduction One in four women veteran patients experience public harassment by men veterans at Veterans Affairs (VA) health care facilities. Bystander intervention training—teaching bystanders to identify harassment, assess appropriate responses, and safely intervene before, during, or after an event—is a popular strategy for addressing harassment in military and education settings. We explored staff and veteran patient perspectives on bystander intervention training to address harassment of women veterans in VA health care settings. Methods We conducted 24 staff interviews and 15 veteran patient discussion groups (eight men's groups and seven women's groups) at four VA Medical Centers. We analyzed transcripts using the constant comparative method. Results Participants expressed divergent views about bystander intervention training to address harassment of women veteran patients at VA. Most participants supported training staff in bystander intervention, but support for training patients was mixed. Participants identified potential benefits of bystander intervention, including staff and patient empowerment and improvements to organizational culture. They also identified potential concerns, including provocation of conflict between patients, lack of buy-in among the VA community, and difficulty in identifying intervention-appropriate situations. Finally, participants offered recommendations for tailoring training content and format to the VA context. Conclusions Bystander intervention training has the potential to raise collective responsibility for addressing harassment of women in VA and other health care contexts. However, our results illustrate divergent stakeholder views that underscore the importance of engaging and educating stakeholders, securing buy-in, and tailoring bystander intervention programs to local contexts before implementation.

Introduction The Radiofrequency Vapor Ablation (RFVA) System (AquaMedical, Inc., Santa Ana, CA) is a novel ablation system for eradication of Barrett’s esophagus, that generates vapor at 100 °C using an RF electrode located in the catheter tip. We performed in-vitro dosimetry studies and the first in-human feasibility study. Methods The system includes an RFVA generator with syringe pump and a through-the-scope-catheter. The RFVA system was tested in-vitro (lean-beef and porcine study) and ablation depth was compared to focal RFA. Two doses were selected for further in-vivo testing in dysplatic BE patients. Repeat endoscopy with histology was performed after 8 weeks to assess squamous conversion. Results In porcine, RFVA 3-seconds was comparable to RFA, whereas RFVA 5-seconds produced slightly deeper ablation. We selected a conservative 1-second and 3-seconds for human study. Fifty-three ablations were successfully applied in 15 patients with no adverse events. Follow-up endoscopy showed a median squamous conversion of 55 % (IQR 33 – 74) and 98 % (56 – 99) for 1 and 3-seconds, respectively. Conclusions In this 3-phase study with lean-beef, porcine and the first in-human application, the RFVA system was feasible for esophageal ablation and successfully and safely converted targeted BE areas into squamous epithelium.

Objective: This study is a secondary analysis of data collected in an earlier clinical trial of mindfulness-based resilience training (MBRT) (ClinicalTrials.gov registration number 02521454), where the MBRT condition demonstrated a significant reduction in self-reported burnout and trend-level reductions in alcohol use in law enforcement officers (LEOs). Given that MBRT is not designed to be a substance use intervention and does not contain explicit substance-related content, this study sought to clarify these findings by exploring whether improved burnout mediates reduced alcohol use. Method: Participants (n = 61) were sworn LEOs (89% male, 85% White, 8% Hispanic/Latinx) recruited from departments in a large urban metro area of the northwestern United States, and were randomized to either MBRT (n = 31) or no intervention control group (n = 30) during the trial. Results: MBRT group assignment predicted reduced burnout (b = 0.43, standard error [SE] = 0.14, p = 0.004), which subsequently predicted reduced alcohol use (b = 1.69, SE = 0.81, p = 0.045). Results suggest that reduced alcohol use was indirectly related to a reduction in burnout post-MBRT. Conclusion: Given that MBRT does not explicitly address substance use, these findings were interpreted to suggest that officers in the training acquired a new set of coping skills to deal with the operational and organizational stressors of police work.

Objectives The aim of this study was to evaluate initial antimicrobial therapy in cats diagnosed with upper or lower bacterial urinary tract infections at veterinary practices in the USA and Canada. Methods Electronic medical records from a veterinary practice corporation with clinics in the USA and Canada were queried between 2 January 2016 and 3 December 2018. Feline patient visits with a diagnosis field entry of urinary tract infection, cystitis and pyelonephritis, as well as variation of those names and more colloquial diagnoses such as kidney and bladder infection, and where an antimicrobial was prescribed, were retrieved. Results Prescription data for 5724 visits were identified. Sporadic cystitis was the most common diagnosis (n = 5051 [88%]), with 491 (8.6%) cats diagnosed with pyelonephritis and 182 (3.2%) with chronic or recurrent cystitis. Cefovecin was the most commonly prescribed antimicrobial for all conditions, followed by amoxicillin–clavulanic acid. Significant differences in antimicrobial drug class prescribing were noted between practice types and countries, and over the 3-year study period. For sporadic cystitis, prescription of amoxicillin–clavulanic acid increased significantly and cefovecin decreased between 2016 and 2018, and 2017 and 2018, while fluoroquinolone use increased between 2017 and 2018. Conclusions and relevance The results indicate targets for intervention and some encouraging trends. Understanding how antimicrobials are used is a key component of antimicrobial stewardship and is required to establish benchmarks, identify areas for improvement, aid in the development of interventions and evaluate the impact of interventions or other changes.

ObjectivesThe risk of suicide among UK military veterans remains unclear. Few recent studies have been undertaken, and most studies found no clear evidence of increased risk. We used data from the Trends in Scottish Veterans Health cohort to investigate suicides up to 2017 in order to examine whether there have been any changes in the long-term pattern of veteran suicides since our earlier study to 2012, and to compare trends in the risk of suicide among veterans with matched non-veterans.MethodRetrospective cohort study of 78 000 veterans and 253 000 non-veterans born between 1945 and 1995, matched for age, sex and area of residence, using survival analysis to examine the risk of suicide in veterans in comparison with non-veterans overall and by subgroup, and to investigate associations with specific mental health conditions.ResultsUp to 37 years of follow-up, 388 (0.5%) veterans and 1531 (0.6%) non-veterans died from suicide. The risk of suicide among veterans did not differ from non-veterans overall. Increased risk among early service leavers was explained by differences in deprivation, and the previously reported increased risk in female veterans is now confined to older women. Suicide was most common in the fifth decade of life, and around 20 years postservice. A history of mood disorder or post-traumatic stress disorder was non-significantly more common in veterans.ConclusionsVeterans are not at increased risk of suicide overall. The highest risk for both men and women is in middle age, many years after leaving service.

Background As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. Methods We describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ß-lactamase (NDM)–5–producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance, using 5 sequential clinical E. coli isolates obtained from the patient. Results In all 5 isolates, blaNDM-5 genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 μg/mL for isolates 1–2, 3, and 4–5, respectively. WGS showed that isolates 1–3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 and 10 copies of the blaNDM-5 gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of blaNDM-5 messenger RNA expression analysis, in which isolates 4 and 5 expressed blaNDM-5 1.7- and 2.8-fold, respectively, compared to, isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was successfully treated with this combination and remained infection free 1 year later. Conclusions The findings in our patient suggest that increased copy numbers of blaNDM genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased blaNDM-5 expression in contributing to cefiderocol resistance needs investigation.

Background and Aims Barrett's esophagus (BE) is accompanied by an increased risk of developing esophageal cancer. Accurate risk‐stratification is warranted to improve endoscopic surveillance. Most data available on risk factors is derived from tertiary care centers or from cohorts with limited surveillance time or surveillance quality. The aim of this study was to assess endoscopic and clinical risk factors for progression to high‐grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in a large prospective cohort of BE patients from community hospitals supported by an overarching infrastructure to ensure optimal surveillance quality. Methods A well‐defined prospective multicenter cohort study was initiated in six community hospitals in the Amsterdam region in 2003. BE patients were identified by PALGA search and included in a prospective surveillance program with a single endoscopist performing all endoscopies at each hospital. Planning and data collection was performed by experienced research nurses who attended all endoscopies. Endpoint was progression to HGD/EAC. Results Nine hundred eighty‐five patients were included for analysis. During median follow‐up of 7.9 years (IQR 4.1–12.5) 67 patients were diagnosed with HGD (n = 28) or EAC (n = 39), progression rate 0.78% per patient‐year. As a clinical risk factor age at time of endoscopy was associated with neoplastic progression (HR 1.05; 95% CI 1.03–1.08). Maximum Barrett length and low‐grade dysplasia (LGD) at baseline were endoscopic predictors of progression (HR 1.15; 95% CI 1.09–1.21 and HR 2.36; 95% CI 1.29–4.33). Conclusion Risk of progression to HGD/EAC in a large, prospective, community‐based Barrett's cohort was low. Barrett's length, LGD and age were important risk factors for progression. (www.trialregister.nl NTR1789)

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study ( NCT03248882 ) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging–proton density fat fraction. Dose-dependent reductions in liver fat reached 50–65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was −7.2 (−13.9, 0.0), −17.1 (−22.7, −11.1), −49.9 (−53.3, −46.2), −55.9 (−59.0, −52.4) and −64.8 (−67.5, −62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) −44.6% (−54.8, −32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was −44.5% (−55.0, −31.7) and −35.4% (−47.4, −20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone. Two phase 2a trials demonstrate the efficacy of a new ACC inhibitor (PF 05221304) for reducing liver fat in patients with NAFLD, with co-administration of a DGAT2 inhibitor (PF-06865571) mitigating ACC inhibitor-mediated increases in serum triglycerides.

Metrics of poor patient engagement, including missed appointments, treatment interruption, sub-optimal medication adherence, and loss to follow-up, have been linked to poor clinical multidrug-resistant TB (MDR-TB) outcomes. Understanding the risk factors for poor patient engagement is necessary to improve outcomes and control TB. This review synthesizes the risk factors for poor patient engagement in MDR-TB treatment across South Africa.A systematic review of five databases (PubMed, Embase, CINAHL, Cochrane, and Web of Science) was conducted, covering articles published between 2010 and 2020. Articles were included if they provided information about risk factors associated with poor engagement among adults (⩾15 years) in treatment for MDR-TB in South Africa. Reviews, editorials, abstracts, and case studies were excluded.Six studies met the inclusion criteria. Male sex and younger age were the most consistently identified risk factors for poor engagement; however, there was a lack of consistency in the choice of covariates, measurement of the variables, analytic methods, and significant factors associated with poor engagement between studies. Alcohol use, substance use, living with HIV, pulmonary TB site, and ethnicity were all identified as risk factors in at least one included study, while formal housing and steady employment were found to be protective.The available literature offers little cohesive data to address poor patient engagement in this population. Further research needs to focus on identifying and addressing risk factors for poor patient engagement. This is particularly salient within the context of newer all-oral and short-course MDR-TB treatment regimens.Les indicateurs d’une faible coopération des patients, tels que les rendez-vous manqués, les arrêts de traitement, une observance thérapeutique sous-optimale et une perte de vue du patient, ont été associés à de mauvais résultats cliniques dans le cadre de la TB multirésistante (MDR-TB). Il convient de comprendre les facteurs de risque d’une faible coopération des patients pour améliorer les résultats et contrôler la TB. Cette revue synthétise les facteurs de risque d’une faible coopération des patients dans le cadre du traitement de la MDR-TB en Afrique du Sud.Une revue systématique de cinq bases de données (PubMed, Embase, CINAHL, Cochrane et Web of Science) a été réalisée, englobant les articles publiés entre 2010 et 2020. Les articles ont été inclus s’ils apportaient des informations sur les facteurs de risque associés à la faible coopération des patients adultes (⩾15 ans) sous traitement pour MDR-TB en Afrique du Sud. Les revues, les éditoriaux, les résumés et les études de cas ont été exclus.Six études satisfaisaient les critères d’inclusion. Les facteurs de risque d’une faible coopération les plus fréquents étaient le genre masculin et le jeune âge. Cependant, un manque de cohérence a été observé entre les études dans le choix des covariables, la mesure des variables, les méthodes analytiques et les facteurs significatifs associés à une faible coopération. La consommation d’alcool et de drogues, la séropositivité au VIH, une TB pulmonaire et l’origine ethnique ont tous été identifiés comme facteurs de risque dans au moins une étude incluse, alors que des facteurs tels que « logement formel » et « emploi stable » étaient des facteurs protecteurs.La littérature disponible offre peu de données cohérentes permettant d’examiner la faible coopération des patients dans cette population. Les recherches à venir doivent identifier et analyser les facteurs de risque de la faible coopération des patients. Ceci est particulièrement important au vu des nouveaux schémas thérapeutiques courts et entièrement par voie orale de la MDR-TB.

Background: Patients with complete rotator cuff tears who fail a course of nonoperative therapy can benefit from surgical repair. Purpose: This randomized trial compared mini-open (MO) versus all-arthroscopic (AA) rotator cuff repair. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Patients with rotator cuff tears were randomized to undergo MO or AA repair at 9 centers by 23 surgeons. The primary outcome (Western Ontario Rotator Cuff Index [WORC]) and secondary outcomes (American Shoulder and Elbow Surgeons [ASES] score, Shoulder Pain and Disability Index [SPADI] pain subscale, 12-Item Short Form Health Survey [SF-12], reported medication use, adverse events), as well as measurements of range of motion and strength, were collected at 1 month before surgery; at 2 and 6 weeks postoperatively; and at 3, 6, 12, 18, and 24 months postoperatively. A blinded radiologist evaluated rotator cuff integrity on magnetic resonance imaging (MRI) at baseline and 1 year. Intention-to-treat analysis of covariance with the preoperative WORC score, age, and tear size as covariates assessed continuous outcomes. Sex differences were assessed. A meta-analysis synthesized the primary outcome between MO and AA repair with previous trials. Results: From 954 patients screened, 411 were ineligible (276 because of recovery with physical therapy), 449 were screened at surgery (175 ineligible), and 274 completed follow-up (138 MO and 136 AA). The AA and MO groups were similar before surgery. WORC scores improved from 40 preoperatively to 89 (AA) and 93 (MO) at 2 years, for an adjusted mean difference of 3.4 (95% CI, –0.4 to 7.2). There were no statistically significant differences between the AA and MO groups at any time point. All secondary patient-reported outcomes were not significantly different between the MO and AA groups, except the 2-year SPADI pain score (8 vs 12, respectively; P = .02). A similar recovery in range of motion and strength occurred in both groups over time. MRI indicated minimal improvement in muscle relative to fat (AA: n = 3; MO: n = 2), with most worsening (AA: n = 25; MO: n = 24) or remaining unchanged (AA: n = 70; MO: n = 70). Opioid use was significantly reduced after surgery (from 21% to 5%). The meta-analysis indicated no significant standardized mean difference between groups in the primary outcome across all pooled studies (standardized mean difference, –0.06 [95% CI, –0.34 to 0.22]). Conclusion: Both AA and MO rotator cuff repair provide large clinical benefits, with few adverse events. There is strong evidence of equivalent clinical improvements. Trial Registration: NCT00128076.

BACKGROUND Timely recognition of sepsis and identification of pathogens can improve outcomes in critical care patients but microbial cultures have low accuracy and long turnaround times. In this proof-of-principle study, we describe metagenomic sequencing and analysis of nonhuman DNA in plasma. We hypothesized that quantitative analysis of bacterial DNA (bDNA) levels in plasma can enable detection and monitoring of pathogens. METHODS We enrolled 30 patients suspected of sepsis in the surgical trauma intensive care unit and collected plasma samples at the time of diagnostic workup for sepsis (baseline), and 7 days and 14 days later. We performed metagenomic sequencing of plasma DNA and used computational classification of sequencing reads to detect and quantify total and pathogen-specific bDNA fraction. To improve assay sensitivity, we developed an enrichment method for bDNA based on size selection for shorter fragment lengths. Differences in bDNA fractions between samples were evaluated using t test and linear mixed-effects model, following log transformation. RESULTS We analyzed 72 plasma samples from 30 patients. Twenty-seven samples (37.5%) were collected at the time of infection. Median total bDNA fraction was 1.6 times higher in these samples compared with samples with no infection (0.011% and 0.0068%, respectively, p < 0.001). In 17 patients who had active infection at enrollment and at least one follow-up sample collected, total bDNA fractions were higher at baseline compared with the next sample (p < 0.001). Following enrichment, bDNA fractions increased in paired samples by a mean of 16.9-fold. Of 17 samples collected at the time when bacterial pathogens were identified, we detected pathogen-specific DNA in 13 plasma samples (76.5%). CONCLUSION Bacterial DNA levels in plasma are elevated in critically ill patients with active infection. Pathogen-specific DNA is detectable in plasma, particularly after enrichment using selection for shorter fragments. Serial changes in bDNA levels may be informative of treatment response. LEVEL OF EVIDENCE Epidemiologic/Prognostic, Level V.

This study assessed the environmental impacts and economic feasibility of generating heat using wood-briquettes (WBs), and heat and electricity using torrefied-wood-briquettes (TWBs). WBs and TWBs were manufactured from forest residues using portable systems and delivered to either residential consumers or power plants in the United States. An integrated cradle-to-grave life-cycle assessment (LCA) and techno-economic analysis (TEA) approach was used to quantify environmental impacts and minimum-selling prices (MSPs) of heat and electricity, respectively. Results illustrated that 82% and 59% of the cradle-to-grave global warming (GW) impact of producing heat resulted from the feedstock preparation in WBs and torrefaction in TWBs, respectively. About 46–54% of total cost in the production of heat were from labor and capital costs only. The GW impact of electricity production with TWBs was dominated by the torrefaction process (48% contribution). Capital cost (50%) was a major contributor to the total cost of electricity production using TWBs. The GW impacts of producing heat were 7–37 gCO₂eq/MJ for WBs, and 14–51 gCO₂eq/MJ for TWBs, whereas producing electricity using TWBs was 146–443 gCO₂eq/kWhe. MSPs of generating heat from WBs and TWBs were €1.09–€1.73 and €1.60–€2.26/MJ, respectively, whereas the MSP of electricity from TWBs was €20–€25/kWhe. Considering carbon and pile-burn credits, MSPs of heat and electricity were reduced by 60–90% compared to the base-case.

Twiddler’s syndrome (TS) is a hardware-related complication of deep brain stimulation which has not been well documented and is probably underreported. The objective of this study is to comprehensively describe TS by systematically reviewing the related literature. The methods include selecting the eligible studies based on the inclusion and exclusion criteria. Data about studies and TS were collected. A descriptive statistical analysis of the extracted data was performed. We found 18 eligible studies describing 23 patients with TS. The mean age of the 23 patients was 61.4 ± 15.9 years (range, 16–79 years.). The percentage of TS in the female population was 91.3% (females: 21/23). The incidence of postoperative TS was 1.4% (6 out of 437) per patient and 1.1% (8 out of 709) per extension wire. The mean time to clinical presentation was 9.9 ± 10.3 months (range, 0.5–36 months). Nineteen of the twenty-three patients presented with a rebound of previous symptoms. Twelve of the twenty-three patients had high impedance at the postoperative checkup of the DBS system. A plain X-ray indicated twisted extension wires in almost all these patients. All patients meeting the definition of postoperative device-related TS underwent revision surgery. TS is more prevalent in females. Based on the typical clinical symptoms (rebound of the previous symptoms, high impedance, and X-ray demonstration), the differential diagnosis can often be straightforward. TS should thus be taken into consideration when attempting to explain or rule out hardware malfunction. The timely recognition and proper revision of TS can prevent further serious damage.

To study transitions from and to chronic widespread pain (CWP) over 7 years in patients with rheumatoid arthritis (RA).Two postal questionnaires were sent to patients included in the BARFOT (Better Anti-Rheumatic Pharmacotherapy) study, the first in 2010 and the second in 2017. The questionnaires assessed pain, number of tender and swollen joints, functional disability, health-related quality of life (HRQoL), pharmacological treatment, lifestyle factors, and patient-reported body mass index (BMI). The responders to both questionnaires were divided into three groups according to the reported pain duration and distribution: patients having no chronic pain (NCP), chronic regional pain (CRP), and CWP.In all, 953 patients answered the questionnaires at both time-points. One-third (324) of the patients reported CWP in 2010, and 140 (43%) of the patients had transition to NCP or CRP in 2017. In multivariate logistic regression models, adjusting for age, gender, and disease duration, transition from CWP was associated with normal BMI, fewer tender joints, less pain, less fatigue, fewer pain regions, less disability, better HRQoL, and biologic treatment. In 2010, 628 patients reported NCP or CRP, whereas 114 of them reported CWP in 2017. Transition to CWP was associated with female gender, obesity, more tender and swollen joints, higher pain-related variables, worse disability, and worse HRQoL.There are modifiable factors associated with transitions from and to CWP that could be identified. Paying attention to these factors could improve pain treatment in the management of RA.

Avascular necrosis of the scaphoid, often referred to as Preiser's disease, is little known despite the scaphoid being the second most frequently involved location in avascular pathology of the carpal bones after the lunate (Kienböck's disease). Nonetheless, very few cases have been reported in the medical literature over the last century. Its pathophysiology is not completely elucidated although the unique vascularization of the scaphoid and several risk factors seem to be recurrently incriminated. Two new classifications based on modern imaging have appeared in the last decade and are now considered essential supplements to Herbert and Lanzetta's original radiographic classification. Because of the lack of formal treatment guidelines, a wide range of different treatments have been explored over time, contributing to the confusion around this pathology. Adding to this confusion, are the numerous terms used to designate the condition and lack of knowledge concerning its pathophysiology, risk factors, clinical and radiographic presentation. The aim of this review is therefore to explore and clarify Preiser's disease in terms of history, terminology, pathophysiology, clinical considerations and imaging and to propose a simple updated treatment algorithm based on the results provided by a thorough review of literature (53 publications, 170 patients) since Georg Preiser's original and controversial description in 1910.

Background Antimicrobials are commonly used to treat urinary tract disease in dogs. Understanding antimicrobial use is a critical component of antimicrobial stewardship efforts. Hypothesis/objectives To evaluate antimicrobial prescriptions for dogs diagnosed with acute cystitis, recurrent cystitis, and pyelonephritis. Animals Dogs prescribed antimicrobials for urinary tract disease at veterinary practices in the United States and Canada. Materials and methods A retrospective review of antimicrobial prescriptions was performed. Results The main clinical concerns were sporadic bacterial cystitis (n = 6582), recurrent cystitis (n = 428), and pyelonephritis (n = 326). Amoxicillin/clavulanic acid (2702, 41%), cefpodoxime (1024, 16%), and amoxicillin (874, 13%) were most commonly prescribed for sporadic bacterial cystitis. The median prescribed duration was 12 days (range, 3-60 days; interquartile range [IQR], 4 days). Shorter durations were used in 2018 (median, 10 days; IQR, 4 days) compared to both 2016 and 2017 (both median, 14 days; IQR, 4 days; P ≤ .0002). Amoxicillin/clavulanic acid (146, 33%), marbofloxacin (95, 21%), and cefpodoxime (65, 14%) were most commonly used for recurrent cystitis; median duration of 14 days (range, 3-77 days; IQR, 10.5 days). Amoxicillin/clavulanic acid (86, 26%), marbofloxacin (56, 17%), and enrofloxacin (36, 11%) were most commonly prescribed for pyelonephritis; however, 93 (29%) dogs received drug combinations. The median duration of treatment was 14 days (range, 3-77 days; IQR, 11 days). Conclusions and clinical importance Decreases in duration and increased use of recommended first-line antimicrobials were encouraging. Common drug choices and durations should still be targets for antimicrobial stewardship programs that aim to optimize antimicrobial use, concurrently maximizing patient benefits while minimizing antimicrobial use and use of higher tier antimicrobials.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract. Funding: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, Rockefeller University; the St. Giles Foundation; the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at the George Mason University; the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956); the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01) and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (EQU201903007798); the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects; the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 824110 (EASI-genomics). The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Neurometabolic Diseases Laboratory received funding from the European Union’s Horizon 2020 Research and Innovation Program (EasiGenomics grant no. 824110 COVID-19/PID12342). A.P., R.P.d.D., C.R.-G., and C.F. were funded by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación DISA (OA18/017), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). The laboratories of G.N. and A.N. were supported by a grant awarded to Regione Lazio (PROGETTI DI GRUPPI DI RICERCA 2020) no. A0375-2020-36663, GecoBiomark. A. Amara’s laboratory was supported by ANR under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the FRM (EQU202003010193), ANR (ANR-20-COVI-000 project IDISCOVR and ANR-20-CO11-0004 project FISHBP), and the University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVID-SOUL). This work was supported, in part, by the Division of Intramural Research, NIAID, NIH (grants 1ZIAAI001265 to H.C.S. and ZIA AI001270 to L.D.N.). The G.C. laboratory was supported by the Italian Ministry of Health (grant COVID-2020-12371617) and the intramural COVID Host Genetics program. The J.L.F. laboratory was supported, in part, by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX; 806-2018) and Colciencias contract 713-2016 (no. 111574455633). The V.S. laboratory was supported by ANR DENDRISEPSIS (ANR-17-CE15-0003) and ANR APCOD (ANR-17-CE15-0003-01), a Fast Grant from the Mercatus Center, FRM, University of Paris PLAN D’URGENCE COVID19. The N.M. laboratory was supported by Sidra Medicine (SDR400048) and the Qatar National Research Fund (grant No. NPRP9-251-3-045)

Background Percutaneous occlusion of ductus arteriosus is well established as the method of choice to treat this structural heart defect. A new generation of Amplatzer™ Duct Occluder II Aditional Sizes prostheses, with lower profile and greater flexibility, in addition to smaller retention discs, was developed for percutaneous treatment of patent ductus arteriosus. This study intended to demonstrate the experience of one center with the use of this device, evaluating technical aspects, immediate occlusion rates, and complications. Methods A retrospective study of a cohort of patients with patent ductus arteriosus treated with Amplatzer™ Duct Occluder II Aditional Sizes. Between October 2018 and March 2021, 27 patients with patent ductus arteriosus, types A and E according to the Krichenko classification, were treated with Amplatzer™ Duct Occluder II Aditional Sizes. The prosthesis was implanted by the usual anterograde approach in 25 patients, and retrograde in two cases. The prosthesis chosen were 2mm larger than the core of the defect, and the length of the prosthesis was 2mm for shorter lesions and smaller infants, and between 4 and 6mm for longer lesions. Results Out of 27 patients, 52% were female, with a mean age and weight of 44.2 months (1 to 135 months) and 15.8kg (2,0 to 29kg), respectively. In the sample, 11 patients presented type A patent ductus arteriosus, and 16 type E, with a mean ratio of 1.9:1 between the prosthesis waist and the central diameter. In all patients, the device was successfully implanted, and only one patient remained with residual shunt, presenting embolization of the prosthesis. This patient had the ductus arteriosus closed by another prosthesis. Conclusion Amplatzer™ Duct Occluder II Aditional Sizes demonstrated safety, versatility, and efficiency in cases of appropriate anatomy. The experience demonstrated here is from a single center, with the Amplatzer™ Duct Occluder II Aditional Sizes. Its increased flexibility and softness demand greater operator expertise.

Background Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 dia...

International audience; Although follicular lymphoma (FL) is usually graded as FL1-2, FL3A, and FL3B, some borderline cases can be observed and led us to investigate the clinicopathologic diversity of grade 3 FL (FL3). Among 2449 FL patients enrolled in Lymphoma Study Association (LYSA) trials, 1921 cases with sufficient material underwent a central pathologic review. The resulting diagnoses comprised 89.6% FL1-2 (n=1723), 7.2% FL3A (n=138), and 0.5% purely follicular FL3B (n=9). The remaining 51 unclassifiable cases (2.7%) exhibited high-grade features but did not meet WHO criteria for either FL3A or FL3B; and were considered as “unconventional” high-grade FL (FL3U). FL3U morphological pattern consisted of nodular proliferation of large cleaved cells or small-sized to medium-sized blast cells. Compared with FL3A, FL3U exhibited higher MUM1 and Ki67 expression, less BCL2 breaks and more BCL6 rearrangements, together with a higher number of cases without any BCL2, BCL6 or MYC rearrangement. FL3U harbored less frequent mutations in BCL2, KMT2D, KMT2B, and CREBBP than FL3A. MYC and BCL2 were less frequently mutated in FL3U than FL3B. Rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone treated FL3U patients had a worse survival than FL1-2 patients with similar follicular lymphoma international prognostic index and treatment. These results suggest that high-grade FLs encompass a heterogeneous spectrum of tumors with variable morphology and genomic alterations, including FL3U cases that do not strictly fit WHO criteria for either FL3A or FL3B, and display a worse outcome than FL1-2. The distinction of FL3U may be useful to allow a better comprehension of high-grade FLs and to design clinical trials.

Deep brain stimulation (DBS) is currently a standard procedure for advanced Parkinson’s disease. Many centers employ awake physiological navigation and stimulation assessment to optimize DBS localization and outcome. To enable DBS under sedation, asleep DBS, we characterized the cortico-basal ganglia neuronal network of two nonhuman primates under propofol, ketamine, and interleaved propofol-ketamine (IPK) sedation. Further, we compared these sedation states in the healthy and Parkinsonian condition to those of healthy sleep. Ketamine increases high-frequency power and synchronization while propofol increases low-frequency power and synchronization in polysomnography and neuronal activity recordings. Thus, ketamine does not mask the low-frequency oscillations used for physiological navigation toward the basal ganglia DBS targets. The brain spectral state under ketamine and propofol mimicked rapid eye movement (REM) and Non-REM (NREM) sleep activity, respectively, and the IPK protocol resembles the NREM-REM sleep cycle. These promising results are a meaningful step toward asleep DBS with nondistorted physiological navigation.

BACKGROUND: Dynamic cerebral autoregulation and cerebral perfusion pressure are altered in pregnancies complicated by preeclampsia compared with normotensive pregnancies, but the connections of dynamic cerebral autoregulation, cerebral perfusion pressure, and cerebral complications in preeclampsia remain unclear.OBJECTIVE: This study aimed to assess dynamic cerebral autoregulation and cerebral perfusion pressure after delivery in women with eclampsia, in women with preeclampsia both with and without severe features, and in normotensive women.STUDY DESIGN: This was a prospective case control study at a large referral hospital in Cape Town, South Africa. The recruitment of participants was done at diagnosis (cases) or at admission for delivery (controls). Transcranial Doppler examinations with continuous noninvasive blood pressure measurements and end-tidal CO2 monitoring were conducted for cases and controls after delivery. Cerebral perfusion pressure and dynamic cerebral autoregulation index were calculated, and values were compared among groups.RESULTS: We included 16 women with eclampsia, 18 women with preeclampsia with severe features, 32 women with preeclampsia without severe features, and 21 normotensive women with uncomplicated pregnancies. Dynamic cerebral autoregulation was depressed in pregnant women with eclampsia; (autoregulation index, 3.9; interquartile range, 3.1-5.2) compared with all other groups (those with preeclampsia with severe features, autoregulation index, 5.6 [interquartile range, 4.4-6.8]; those with preeclampsia without severe features, autoregulation index, 6.8 [interquartile range, 5.1-7.4]; and normotensive controls, autoregulation index, 7.1 [interquartile range, 6.1-7.9]). Pregnant women with eclampsia had increased cerebral perfusion pressure (109.5 mm Hg; interquartile range, 91.2-130.9) compared with those with preeclampsia without severe features and those with normal blood pressure (84 mm Hg [interquartile range, 73.0-122.0] and 80.0 mm Hg [interquartile range, 67.5-92.0], respectively); furthermore, there was no difference in cerebral perfusion pressure between pregnant women with eclampsia and pregnant women with preeclampsia with severe features (109.5 mm Hg [interquartile range, 91.2-130.9] vs 96.5 mm Hg [interquartile range, 75.8-110.5]).CONCLUSION: Cerebral perfusion pressure and dynamic cerebral autoregulation are altered in eclampsia and may be important in the pathophysiological pathway and constitute a therapeutic target in the prevention of cerebral complications in preeclampsia.